Antimicrobial agents to combat tough-to-treat Gram-negative infections are urgently needed. The current Gram-negative antibiotics have become less effective due to a widespread bacterial resistance. The new antibacterial should possess useful levels of activity against certain human and veterinary pathogens, including Gram-negative pathogens implicated in serious infections, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiela pneumoniae. 
Among other antibacterials, polymyxins stand out for their high potency against Gram-negative pathogens, including Pseudomonas aeruginosa. This class is comprised of several structurally related cyclic peptide analogs, including polymyxin B (PMB) and polymyxin E (colistin), as described, for example, by Velkov et al. in J. Med. Chem., 2010, vol. 53, pp. 1898-1916.
Unfortunately, while being highly potent against bacteria, polymyxins suffer from toxicity inherent in the cationic peptide class. This leads to the high frequency of serious adverse effects, chiefly due to a persistence of polymyxins in vivo after administration to a mammal or human, with predominant accumulation of these agents in kidneys.
The accumulation of colistin in kidney tissues causes severe side effects, up to and including the organ failure. Provided herein are new polymyxin compounds with significantly improved safety and reduced propensity for adverse effects, as compared to other polymyxin pharmaceuticals.
Various polymyxin derivatives and structurally related cyclopeptides have been described, for example, in publications WO 2015/149131, WO 2015/135976, US 2015/0031602, WO 2014/188178, WO 2014/108469, CN 103923190, US 2014/0162937, WO 2014/028087, WO 2013/112548, CN 103130876, WO 2013/072695, WO 2012/168820, WO 2012051663, US 2012/0283176, US 2010/0160215, US 2009/0215677, WO 2008/017734, WO 2006/045156, US 2006/0004185, U.S. Pat. No. 6,380,356, and U.S. Pat. No. 3,450,687. None of these references specifically describe or generally contemplate the compounds of the present invention, nor the new concept for reducing nephrotoxicity of the polymyxin antibiotics provided herein.